Dr Andrew Cowburn

I have recently characterised a lung endothelial specific knock-out of HIFa isoforms to determine their role in pulmonary hypertension.  Hypoxic pulmonary vasoconstriction initiates pulmonary vascular remodelling, which when prolonged leads to the development of pulmonary hypertension.  The hypoxia-inducible transcription factors (HIFs), HIF-1α and HIF-2α are known to contribute to the process of hypoxic pulmonary vascular remodelling, but the specific role of pulmonary endothelial HIF expression in this process has not been studied. I have shown that pulmonary endothelial HIF-2α is a critical regulator of hypoxia-induced pulmonary arterial hypertension (PAH). The rise in right ventricular systolic pressure (RVSP) normally observed following chronic hypoxic exposure was absent in mice with pulmonary endothelial HIF-2α deletion. The RVSP of mice lacking HIF-2α in pulmonary endothelium after exposure to hypoxia was not significantly different from normoxic wild type (WT) mice and much lower than the RVSP values seen in WT littermate controls and mice with pulmonary endothelial deletion of HIF-1α exposed to hypoxia. Minimal pulmonary vascular remodelling was observed in lungs of mice with pulmonary endothelial deletion of HIF-2α following chronic hypoxia. These data offer new insight into the role of pulmonary endothelial HIF-2α in regulating the pulmonary vascular response to hypoxia.